The invention relates to transgenic mammals characterized by 5-HT3 receptor over-expression in the central nervous system (CNS). In particular, the invention relates to such transgenic mammals having a significantly reduced desire for alcohol as compared to mice of the corresponding non-transgenic line.
1. Field of the Invention
5-HT3 receptors belong to a group of receptor subtypes for 5-hydroxytryptophan (serotonin). 5-HT3 receptors are primarily located presynaptically, and are known to modulate the release of a number of neurotransmitters, including GABA, acetylcholine, and dopamine. The receptors are ion-channel-coupled receptors, the only known receptors of this type in the serotonin family.
It is not yet clear how neurotransmitters such as serotonin regulate neuronal cell function. However, 5-HT3 receptors are believed to play a role in neurochemical reward pathways associated with the phenomena of drug abuse and other clinical conditions by modulating dopamine release in the mesolimbic pathway.
2. Discussion of Related Art
Many drugs of abuse, including alcohol, result in the release of dopamine in the nucleus accumbens of the brain, a region associated with motivation and reward. 5-HT3 receptor antagonists have been shown to cause a dose-dependent decrease in alcohol-stimulated dopamine release in the nucleus accumbens (Eur. J. Pharmacol. 187: 287-289, 1990; Alcohol 9: 17-22), and it appears that certain 5-HT3 agonists can stimulate dopamine release in the nucleus accumbens (Brain Res. 513: 156-160, 1990). Nicotine and opiates such as morphine also release dopamine in the nucleus accumbens, and this release can be blocked by 5-HT3 receptor antagonists (Eur. J. Pharmacol. 164: 515-519, 1989).
Animal studies have demonstrated that 5-HT3 receptor antagonists can decrease alcohol self-administration (Alcohol 26: 107-110, 1991; and others). In human studies, 5-HT3 receptor antagonists decreased pleasurable effects of alcohol and increased abstinence in mild alcoholics (Psychopharmacol. 112: 142-144, 1993; Alcohol Clin. Exp Res. 18: 879-855, 1994). Also, 5-HT3 antagonists enhanced the subjective feeling of intoxication produced by ethanol in at least one study (Biol. Psychiatry 40: 514-521, 1996).
5-HT3 antagonists have been proposed for treatment of drug withdrawal syndromes, chemotherapy and drug-induced nausea and emesis, and as antimigraine, anxiolytic, and antipsychotic agents (reported in U.S. Pat. No. 5,057,519 to Suberg, et al.).
Studies of the 5-HT3 receptor have, however, been hampered by the low level of their normal expression in the CNS. 5-HT3 receptors are expressed throughout the forebrain in extremely low amounts. The highest amounts of 5-HT3 receptors appear to be present in the cingulate cortex, entorhinal cortex, hippocampus, and amygdala; the last has also been associated with drug abuse, but 5-HT3 receptors in this brain region have been less well characterized than those in the nucleus accumbens, where 5-HT3 receptors are particularly scarce.
The inventions comprise transgenic mammals carrying an exogenous 5-HT3 transgene in their genome for over-expression in the CNS, particularly the forebrain. The inventions further comprise mammalian embryos carrying the 5-HT3 transgene capable of developing into viable transgenic animals whose progeny carry the transgene after breeding forward by sexual reproduction. The inventions additionally include DNA constructs comprising selected promoter+intron+5-HT3 cDNA or DNA segments cloned into plasmids for ultimate insertion into the genome of a mammal.
The transgenic mammals of the invention are characterized by a high density of functional 5-HT3 receptors in the CNS of the mammals. They also exhibit a decreased desire for alcohol as compared to genetically similar non-transgenic mammals and decreased aggressiveness.